Epidural Steroid Injections for Low Back Pain: A Narrative Review

Low back pain represents a significant socioeconomic burden. Several nonsurgical medical treatments have been proposed for the treatment of this disabling condition. Epidural steroid injections (ESIs) are commonly used to treat lumbosacral radicular pain and to avoid surgery. Even though it is still not clear which type of conservative intervention is superior, several studies have proved that ESIs are able to increase patients’ quality of life, relieve lumbosacral radicular pain and finally, reduce or delay more invasive interventions, such as spinal surgery. The aim of this narrative review is to analyze the mechanism of action of ESIs in patients affected by low back pain and investigate their current application in treating this widespread pathology.


Introduction
Low back pain (LBP) and lumbosacral radicular pain are common causes of physical and mental morbidity and they are also a significant economic burden, causing an expenditure of more than USD 100 billion per year in the United States alone [1,2]. In the medical literature, low back pain is referred to as sciatica, lumbosacral radicular syndrome, lumbar radiculopathy, nerve root pain and nerve root entrapment/irritation, and is commonly described as a pain starting in the back and radiating to the legs. The etiological cause of low back pain is first represented by intervertebral disk disease. The pathophysiological changes involved in the intervertebral disk disease may lead to disk herniation or degenerative diseases, such as canal stenosis or chronic instability of the diseased segments. The most common cause of sciatica is the herniation of the nucleus pulposus, a component of the intervertebral disk in the lumbar region, which causes stenosis and inflammation [3,4]. Some estimate that sciatica caused by herniation of the lumbar disk has a prevalence of 9.8 out of 1000 [5], meaning that of all reported cases of sciatica it appears that 90% are caused by herniation of the lumbar disk [6].
Several nonsurgical medical treatments have been proposed for lumbosacral radicular pain, from lifestyle changes, exercise and physical therapy to analgesic local/oral drugs and epidural steroid injections (ESIs) [7,8]. The conservative management of LBP aims to delay or avoid surgery. As a matter of fact, LBP can improve spontaneously or with Int. J. Environ. Res. Public Health 2022, 19, 231 2 of 17 conservative treatment. Cases which do not respond to treatment are candidates for surgical intervention.
An ESI is a common and minimally invasive procedure, performed to successfully treat lumbosacral radicular pain, which has also proved its effectiveness in the treatment of back acute pain and leg symptoms. The injections are used to deliver steroids, and sometimes local anesthetics, to the epidural space, directly to the site that causes the pain using a caudal, interlaminar or transforaminal approach [9]. The epidural injection is a well-founded anesthetic and analgesic technique; moreover, nowadays, new technological devices can help anesthesiologists to learn and to administer it [10][11][12][13][14][15][16]. Even though it is still not clear which type of conservative intervention is superior, several studies have proved that an ESI is able to increase patients' quality of life, relieve lumbosacral radicular pain and finally, reduce or delay more invasive interventions, such as spinal surgery. Although ESIs should represent a treatment of choice in the case of acute LBP or leg pain, in our research we focused on the efficacy of ESIs in the treatment of chronic LBP.
The aim of this narrative review is to analyze the mechanism of action of ESIs in chronic lumbar pain patients and to understand their current use, application and success in treating this significant widespread pathology.

Materials and Methods
A literature review using online databases was carried out regarding the use of epidural steroid injections for lumbar canal stenosis and disk herniation. Articles were extracted from PubMed, Google Scholar, MEDLINE, UpToDate, Embase and Web of Science, combining the terms "spinal disease," "radicular pain," "spinal stenosis," "canal stenosis," "disk herniation" and "epidural steroid injection" as keywords for the research. Only papers in the English language and regarding human studies were taken into consideration. Non-English language studies were excluded. Scientific publications up to September 2021were included. Only papers focusing on epidural steroid injections for lumbar canal stenosis or disk herniation were included. All reference lists of the relevant studies were then screened to identify any missing publications. The search and the study selection were performed by two investigators (G.P.; A.S.) working independently. At the first level, the titles and abstracts of identified studies were screened. At the second level, the full texts were retrieved and assessed. Ethical approval and patient informed consent were not required because this was a review of previously published studies and did not involve direct contact with patients or alterations to patient care. Any discrepancies were resolved by a third author (M.C.) through consensus. The following data were extracted from each eligible study: first author's name; publication year; study design; intervention protocol type (the type and amount of steroid and local anesthetic used for the ESI and therapies or medication used for conservative treatment); outcome parameters including Visual Analogic Scale (VAS), Numeric Rating Scale (NRS), Oswestry Disability Index (ODI) and successful events; and the summary of findings.

Mechanism of Lumbosacral Radicular Pain
Low back pain and radicular pain are caused by interrelated biomechanical and biochemical factors. With the advancement of age and the presence of chronic diseases such as diabetes, obesity, smoking and overload, a series of degenerative processes occur inside the intervertebral disk [17]. The intervertebral disk is approximately 7 to 10 mm thick and 4 cm in diameter and is formed of two different components: the nucleus pulposus, rich in water and glycopeptides, and the anulus fibrosus, constituted of a series of 15 to 25 rings, or lamellae, with collagen fibers parallel to the lamellae in addition to elastin fibers. A thin hyaline cartilage endplate is the interface between the disk and the superior and inferior vertebrae bodies. When the nucleus becomes less elastic and the anulus less continent due to aging, dehydration, inflammatory conditions and/or prolonged misusage of the back, a part of the nucleus can herniate, usually backward. This causes an inflammatory state in the epidural space and the increase in cytokines and other inflammation mediators. This condition, on the one hand favors the ulterior herniation of the nucleus pulposus and on the other, it compresses and stimulates the spinal nerve roots, resulting in back and radicular pain [18,19].
Generally, sciatica from lumbar disk herniation is a self-limiting condition that improves in weeks or months without medical intervention; in some cases, rest, analgesic drugs and a structured exercise program may be needed. Usually, the inflammatory state is more important than the mechanical compression in the pathogenesis and the chronicity of the disease, unless there are no neurological deficits [20]. However, in patients who are refractory to conservative treatment, surgery is usually recommended.
Lumbar spinal canal stenosis is a process that could be part of the aging process and can be related to herniation of an intervertebral disk. Other common causes of stenosis are: congenital deformities; spondylolisthesis; osteophytes; arthritic degeneration; synovial cysts; hypertrophy of the facet joints; hypertrophy of the ligamentum flavum; epidural lipomatosis; spondylosis of the intervertebral disk margins; previous surgery; and neoplastic diseases. All these factors could cause lumbar nerve root compression with microvascular ischemia, axonal injury, intraneural fibrosis and an inflammatory state, leading to chronic back pain [21].

Rationale of Epidural Steroid Injections
Epidural injections are performed using a Tuohy needle with the tip placed inside the epidural space, which is located between the ligamentum flavum and the dura mater. Usually, the epidural space is localized thanks to the loss of resistance (LOR) technique, where the needle is advanced between the spinal processes of the vertebras with the help of a syringe full of air or saline solution, which is used to continuously test the pressure on the piston of the syringe. The needle passes through the ligamentum flavum and, when the epidural space is reached, a loss of resistance is felt by the operator on the syringe piston. Moreover, epidural injections can also be performed rapidly under CT and navigation guidance ( Figure 1). These techniques can be used to precisely guide needle placement, allowing for the visualization of the optimal needle path and identification of potential problems, such as narrow intralaminar spaces and spinal stenosis, before needle insertion ( Figure 2). inferior vertebrae bodies. When the nucleus becomes less elastic and the anulus less continent due to aging, dehydration, inflammatory conditions and/or prolonged misusage of the back, a part of the nucleus can herniate, usually backward. This causes an inflammatory state in the epidural space and the increase in cytokines and other inflammation mediators. This condition, on the one hand favors the ulterior herniation of the nucleus pulposus and on the other, it compresses and stimulates the spinal nerve roots, resulting in back and radicular pain [18,19].
Generally, sciatica from lumbar disk herniation is a self-limiting condition that improves in weeks or months without medical intervention; in some cases, rest, analgesic drugs and a structured exercise program may be needed. Usually, the inflammatory state is more important than the mechanical compression in the pathogenesis and the chronicity of the disease, unless there are no neurological deficits [20]. However, in patients who are refractory to conservative treatment, surgery is usually recommended.
Lumbar spinal canal stenosis is a process that could be part of the aging process and can be related to herniation of an intervertebral disk. Other common causes of stenosis are: congenital deformities; spondylolisthesis; osteophytes; arthritic degeneration; synovial cysts; hypertrophy of the facet joints; hypertrophy of the ligamentum flavum; epidural lipomatosis; spondylosis of the intervertebral disk margins; previous surgery; and neoplastic diseases. All these factors could cause lumbar nerve root compression with microvascular ischemia, axonal injury, intraneural fibrosis and an inflammatory state, leading to chronic back pain [21].

Rationale of Epidural Steroid Injections
Epidural injections are performed using a Tuohy needle with the tip placed inside the epidural space, which is located between the ligamentum flavum and the dura mater. Usually, the epidural space is localized thanks to the loss of resistance (LOR) technique, where the needle is advanced between the spinal processes of the vertebras with the help of a syringe full of air or saline solution, which is used to continuously test the pressure on the piston of the syringe. The needle passes through the ligamentum flavum and, when the epidural space is reached, a loss of resistance is felt by the operator on the syringe piston. Moreover, epidural injections can also be performed rapidly under CT and navigation guidance ( Figure 1). These techniques can be used to precisely guide needle placement, allowing for the visualization of the optimal needle path and identification of potential problems, such as narrow intralaminar spaces and spinal stenosis, before needle insertion ( Figure 2).   Corticosteroids are widely used in regional anesthesia and chronic pain procedures, such as epidural injections, intraarticular injections and nerve blocks. Corticosteroids have a similar structure and activity to the endogenous produced hormone cortisol, which has an anti-inflammatory, immunosuppressive, vasoconstrictive and antiproliferative effect. They work by preventing the enzyme PLA2 from liberating arachidonic acid from the cells. This inhibits the cyclo-oxygenase and lipoxygenase production, which is responsible for the level of prostaglandins, thromboxanes and leukotrienes, before finally decreasing the inflammatory state [22]. They also inhibit the nerve transmission in nociceptive C fibers and reduce vasal permeability, which decreases intraneural and perineural oedema. Local anesthetics have been administered in the epidural space since 1901; however, the epidural use of corticosteroids has only been documented since 1952 [23]. Their efficacy when administrated via epidural injections has been demonstrated in various studies and a stronger effect has been proven in patients with a higher protein count in the cerebrospinal fluid, which is usually associated with an inflammatory state [24]. The prolonged use of corticosteroids at high doses has many systemic side effects and can also result in iatrogenic adrenal gland suppression; however, the epidural administration limits the systemic side effects because a smaller dose is necessary to reach the pharmacological target and its diffusion into systemic circulation is more difficult than in other types of administration [25]. In the Yang et al. [26] meta-analysis regarding lumbosacral radicular pain due to any cause, the use of ESIs resulted in the more effective in control of lumbosacral pain compared to pure conservative treatment, both in short and intermediate terms.
However, two other recent meta-analyses have shown a similarity in efficacy and Corticosteroids are widely used in regional anesthesia and chronic pain procedures, such as epidural injections, intraarticular injections and nerve blocks. Corticosteroids have a similar structure and activity to the endogenous produced hormone cortisol, which has an anti-inflammatory, immunosuppressive, vasoconstrictive and antiproliferative effect. They work by preventing the enzyme PLA2 from liberating arachidonic acid from the cells. This inhibits the cyclo-oxygenase and lipoxygenase production, which is responsible for the level of prostaglandins, thromboxanes and leukotrienes, before finally decreasing the inflammatory state [22]. They also inhibit the nerve transmission in nociceptive C fibers and reduce vasal permeability, which decreases intraneural and perineural oedema. Local anesthetics have been administered in the epidural space since 1901; however, the epidural use of corticosteroids has only been documented since 1952 [23]. Their efficacy when administrated via epidural injections has been demonstrated in various studies and a stronger effect has been proven in patients with a higher protein count in the cerebrospinal fluid, which is usually associated with an inflammatory state [24]. The prolonged use of corticosteroids at high doses has many systemic side effects and can also result in iatrogenic adrenal gland suppression; however, the epidural administration limits the systemic side effects because a smaller dose is necessary to reach the pharmacological target and its diffusion into systemic circulation is more difficult than in other types of administration [25]. In the Yang et al. [26] meta-analysis regarding lumbosacral radicular pain due to any cause, the use of ESIs resulted in the more effective in control of lumbosacral pain compared to pure conservative treatment, both in short and intermediate terms. However, two other recent meta-analyses have shown a similarity in efficacy and duration, in terms of pain reduction and functional gain, between local anesthetic alone or local anesthetic with a corticosteroid epidural injection [27,28].

Epidural Steroid Injections for Disk Herniation Lumbar Pain
The epidural administration of corticosteroids is one of the most common miniinvasive medical treatments for chronic spinal pain caused by disk herniation [29,30]. In fact, in the absence of chronic severe pain or neurological deficit, epidural steroid injections may be the treatment of choice for disk herniation. As mentioned before, it reduces the concentration of inflammatory mediators in the epidural space and vascular permeability [31]; it also reduces the damage of C fibers, which diminishes the pain [32,33]. In particular, the anesthetic effect of methylprednisolone over other steroids and non-steroid anti-inflammatory drugs has been proven when injected into the epidural space [34].
In clinical practice, both corticosteroids and local anesthetics are used [35,36]; the former are used to reduce the inflammation for a prolonged time, while the latter are used to mitigate the discomfort of the procedure and immediately decrease pain.
The difference in the use of a local anesthetic alone or local anesthetic with a corticosteroid in the epidural administration to treat disk herniation pain has been indagated in numerous papers without a clear result [37,38], although a meta-analysis written by Lee at al. evidenced a small difference between the epidural injection of lidocaine and lidocaine plus corticosteroids [39].
However, a good number of studies have described significant pain relief and improvement of functional status after an ESI, especially in short-medium terms [40][41][42][43][44][45] (Table 1). In fact, Kennedy and colleagues have found a high rate of success of ESIs at 6 months in their study, but there was also a recurrence of the symptoms during the 5 years follow-up after the injection [46]. In a similar way, Buchner et al. found a significant improvement in patients treated with epidural steroid injections for a very short period after the treatment but no improvement was seen after 6 weeks and 6 months, compared to the control group who did not receive the injection [47]. A response to the treatment after 1 h of having the procedure has been suggested as predictive for favorable medium-term success [48]. Interestingly, Buttermann et al. suggested that ESIs could be more effective in patients who presented magnetic resonance imaging of inflammatory endplate changes [49].
On the other hand, the Spine Patient Outcomes Research Trial (SPORT) [50], a prospective multi-center study of the operative versus nonoperative treatment of lumbar intervertebral disk herniation, found no improvement in short-or long-term outcomes in patients who received ESIs compared to patients who did not. However, it is important to say that an increased rate of surgical avoidance was observed in the group treated with ESIs; this could underline the role of conservative treatments, also considering the high incidence of the spontaneous reabsorption of lumbar disk herniation (66.66% according to Zhong et al.) [51].
Finally, Kreiner et al. [52], in their guideline for the diagnosis and treatment of disk herniation with radicular pain, stated that an ESI is indicated for a proportion of patients with lumbar disk herniation to provide symptom relief in the short term (2-4 weeks) with a grade A recommendation. Additionally, at the moment, no sufficient evidence exists to make a recommendation regarding the 12-month, or more, efficacy of ESIs.

Epidural Steroid Injections for Canal Stenosis Lumbar Pain
The administration of steroids via epidural injection as a nonsurgical treatment for lumbar spinal stenosis (LSS) has been analyzed in various studies but, again, there is not a clear consensus regarding their efficacy in relieving the symptoms, especially in the long-term follow-ups. It is important to notice that a consistent number of studies have reported some degree of benefit, especially regarding short-term improvements [53][54][55][56][57][58][59] ( Table 2). A more favorable response seems to be associated with relative youth, female sex and patients with single level stenosis, while BMI, MRI severity and the dimension of the spinal canal are probably not predictive [55,60,61]. Additionally, individual pain sensitivity does not seem to influence the outcome of an ESI in the patients affected by LSS [62]. Interestingly, Milburn and colleagues, in a randomized study, suggested that the response to the treatment is maximized when the ESI is performed at the intervertebral level of maximal stenosis [63], and their result was confirmed by the trial conducted a few years later by Bajpai et al. [64].
A randomized, double-blind controlled trial with a 2-year follow-up was conducted by Manchikanti et al., which compared the epidural injection of local anesthetic alone to local anesthetic plus steroids, and the authors found a significant relief of the symptoms in a convincing percentage of the patients treated, but without significant difference between the two groups [65]. Accordingly, another large randomized trial on 400 patients, conducted by Friedly and colleagues, found minimal or no short-term benefits in adding steroids to a local anesthetic epidural injection for the treatment of LSS [66].
Moreover, some other studies did not find any significant improvement in symptoms or quality of life after an ESI for the treatment of LSS [67][68][69][70]. Tran et al. wrote a review regarding the nonsurgical treatment of LSS and concluded that the literature could provide only limited evidence to formulate recommendations pertaining to the nonsurgical treatment of LSS [71].
Finally, Liu et al., in their systematic review and metanalysis, also concluded that there is minimal evidence to show that epidural steroids are better than local anesthetic alone in the treatment of LSS patients [72]. Randomized parallel-group trial 1.5 mL steroid (not specified) at each site injected. Reassess at 3-4 and 6-8 weeks for potential second and third injections 1.5 mL of steroid (not specified) at each site injected.
Reassess at 3-4 and 6-8 weeks for potential second and third injections + physical therapy (PT) Disability, pain, quality of life and global rating of change were collected at 10 weeks, 6 months and 1 year, and then analyzed using linear mixed model analysis The ESI plus PT was not superior to ESI alone for reducing disability in individuals with LSS. Randomized controlled trial 2 mL 40 mg/mL methylprednisolone + 2 mL bupivacaine 0.25% + 2 mL normal saline at the most stenotic level 2 mL 40 mg/mL methylprednisolone + 2 mL bupivacaine 0.25% + 2 mL normal saline at 2 intervertebral levels cephalad of the level of maximal stenosis Analog pain scale from 0 to 10 during ambulation and at rest, Roland-Morris Disability Questionnaire (RDQ) at baseline, immediately after ESI and at 1, 4, and 12 weeks post-injection Symptom improvement is optimized when the ESI is performed at the intervertebral level of maximal stenosis Bajpai S et al., 2020 [64] Randomized controlled trial 5 mL bupivacaine (0.25%) + 2 mL methylprednisolone acetate (40 mg/mL) + 1 mL normal saline at maximal stenotic intervertebral level 5 mL bupivacaine (0.25%) + 2 mL methylprednisolone acetate (40 mg/mL) + 1 mL normal saline 2 intervertebral levels cephalad to the level of maximal stenosis Numeric Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI) at 2, 6 and 12 weeks after the intervention Pain relief improvement is optimized when the ESI is performed at the maximum stenotic intervertebral level 1 to 3 mL 0.25% to 1% lidocaine followed by 1 to 3 mL triamcinolone (60 to 120 mg), betamethasone (6 to 12 mg), dexamethasone (8 to 10 mg) or methylprednisolone (60 to 120 mg) 1 to 3 mL 0.25% to 1% lidocaine alone RDQ (Roland-Morris Disability Questionnaire), Sickness Impact Profile (SIP) weights assigned to the RDQ items and patient-prioritized RDQ items at 6 weeks after injection No significant difference between groups for the RDQ or patient-prioritized RDQ, and while the difference between groups for RDQ using SIP weights was statistically significant, this was not clinically important

Image-Guided Epidural Injections
Special consideration should be given to image-guided techniques that may help the clinician in performing epidural injections, although no significant difference has been shown regarding outcomes. The use of ultrasound in performing an interlaminar approach could help to estimate the distance from the skin to the epidural space and the optimal needle direction [73,74]. However, although it is a radiation-free technique, ultrasound is limited by the operator's experience and the real-time visualization of needle tip advancement could be challenging, especially in obese patients [75]. Fluoroscopy (x-rays) and computerized tomography (CT) have both proved to be effective and safe techniques for guiding transforaminal epidural injections, although the former provides less radiation exposure for patients [76,77]. Moreover, new generation CT devices may integrate neuronavigation systems that are able to perform a computerized analysis in order to best define the needle's path towards the epidural space. Its use has been described for spinal surgery but it may be expanded to transforaminal epidural injections as well, although the high cost of these devices should be considered [78]. Future studies are expected to determine the best technique in terms of efficacy and safety for both patients and clinicians.

Discussion
Chronic lumbar pain is a widespread problem, which affects a large part of population at some point of their life. Disk herniation and canal stenosis are the most common causes and they need to be treated due to the high impact of the symptoms on patients' quality of life, especially because they could affect walking and ability to work [18].
Surgical intervention has been proven to be effective but is not usually considered as the first option [7]. On the other hand, nonsurgical treatments, such as epidural steroid injections, do not have clear literature consensus. Fully understanding whether ESIs would be able to relieve symptoms and delay or prevent surgery could be a crucial step, especially because chronic back pain patients are typically elderly and multimorbid who could be more affected by the impact of surgery.
In this narrative review, we tried to analyze the existing literature regarding the use ESIs for these kinds of patients, considering randomized controlled studies as well as reviews, meta-analyses and guidelines.
Overall, ESIs seem to be safe and quite effective in relieving the main symptoms, especially in short-term follow-ups, and in delaying surgery, according to a consistent number of studies and to the guideline written by Kreiner and colleagues [52]. Moreover, ESIs could be more powerful in the case of patients with disk herniation than patients with canal stenosis [61]. Attention should also be paid to the technique and to the vertebral level of the injection, at least for spinal stenosis [63,64].
As mentioned before, literature consensus is still missing and numerous studies did not find significative improvements, especially in long-term follow-ups. In addition, it seems to be difficult to find significative differences between using local anesthetics alone or local anesthetics plus steroids in the injection.
Due to the anti-inflammatory action of steroids, patients with high local inflammatory status could probably benefit more from using steroids [49]. However, epidural steroid injections have also been associated with potential adverse effects, including acute neurological symptoms [79,80], in addition to other possible complications related to the epidural technique, i.e., inadvertent dural puncture, hematomas and infection. [81] In this context, the identity of the patients who could benefit the most from this procedure has not been completely established yet and could be a crucial future goal.
This narrative review has some limitations. Firstly, the studies taken into consideration did have different epidural injection approaches. Secondly, the heterogeneity of the enrolled patients, analyzed parameters and data collection in the studies taken into consideration could be an important bias. Lastly, the heterogeneity of the purposes of the studies, such as the comparison of steroid injections versus nothing or local anesthetic injections versus local anesthetic plus steroids, could make global analysis difficult.
Surely, more randomized studies with larger numbers of patients are needed to fully understand the efficacy of ESIs and define which patients could benefit more from the procedure, especially in order to delay or prevent surgery.

Conclusions
According to the literature analyzed in this narrative review, there is no consensus on the use of ESIs for patients with chronic lumbar pain. ESIs seem to be effective in relieving symptoms in the short term and delaying surgery, while evidence of any long-terms benefits is still lacking. More studies are needed to better understand which patients could benefit more from epidural steroid injections.